Oxypurin and process of making same.



UNITED STATES PATENT OFFICE.

EMIL FISCHER, OF BERLIN, GERMANY, ASSIGNOR TO C. F. BOEI-IRINGER dzSOEHNE, OF \VALDHOF, GERMANY.

OXYPURIN AND PROCESS OF MAKING SAME.

SPECIFICATION forming part of Letters Patent N 0. 647,392, dated April10, 1900.

Application filed January 31,1898. Serial No. 668,648. ($pecimens.)

To aZZ whom it may concern.-

Be it known that I, EMIL FISCHER, a citizen of the Empire of Germany,residing at Berlin, in the Empire of Germany, have invented certain newand useful Improvements in the Manufacture of Oxypurins; and I do herebydeclare the following to be a full, clear, and exact description of theinvention, such as will enable others skilled in the art to which itappertains to make and use the same.

The present invention relates to the preparation of oxy-purins and theiralkyl derivatives, and particularly the production of a series of bodiesstarting from trichloropurin, a compound which is described in LettersPatent of the United States No. 598,502, dated February 8, 1898.

My invention has for its specific object the preparation fromtrichloropurin of the dichloro-alkyl-oxypurins, which bodies may bedirectly or indirectly converted into hypoxanthin.

Before proceeding with the description it should be stated that thenomenclature herein followed is that adopted by the article published inBcrichte der Deutschen Ola/emischen Gesellschaft, Vol. 30, page 549.According to this nomenclature a large number of bodiessuch as cafiein,uric acid, guanin, adenin, &c.are designated by the generic termpurins,and their nucleus, the purin group, has its several carbon andnitrogen atoms numbered in the following manner:

Bearing this nomenclature and system of numbering the position of theatoms in the molecule in mind, the use of terms in the followingdescription will be readily understood.

Myinvention consists in the new oxypurin 2-S-dichloro-6-alkyl-oxypurinand the process of preparing the same and in such furforth in myaforesaid Patent, No. 598,502, are

dissolved in sixteen parts of alcohol, and this solution, after beingrapidly cooled to about 10 to 15 centigrade and which, as a rule, has atendency to throw out crystals of the trichloropurin, is added to asolution of one and two-tenths parts-of sodium in twenty-four parts ofalcohol cooled to room temperature.

A clear pale-yellow liquid results, which be- 7 comes spontaneouslyheated to about 30 centigrade and soon becomes turbid by reason of aprecipitation of sodium-chlorid. The mixture is allowed to stand atordinary tem perature for three hours,- whereupon fifty parts of waterare added, and the whole is supersaturated slightly with acetic acid forthe purpose of neutralizing the alkali. Other acids, such ashydrochloric acid and sulfuric acid, may be employed to this end; but inthe case of mineral acids it is to be observed that no heat should beemployed, as otherwise decomposition of the methoxy compound takesplace. The alcohol is then evaporated oif,whereby thedichloro-ethoxy-purin is precipitated in colorless very flexibleacicular crystals. The same is then purified by recrystallization fromhot benzene. Its formula is O I-I OI N,O or

sion being accompanied by decomposition. It is soluble only withdifficulty in hot water,

but dissolves readily in hot alcohol and acetone. I

The above converting process proceeds according to the equation:

N:C.Ol

01.0 O-NH +Nao0,H,:

U 0.01 NO-N N:0.o.0,H,

01.0 ONH +NaCl. i 0 01 l i N-O-N 2 Preparation of2-8-dichloro-d-methowyparin.lf in the place of the ethyl-alcoholicsolution a m ethyl-alcoholic solution of sodium is employed, the otheringredients and conditions of the above process remaining the same, Iobtain 2-8-dichloro-6methoxypurin, which melts and decomposes at about225 centigrade and which is considerably less soluble in benzene thanthe ethoxy compound.

The generic formula for both of the oxyalkyl-diehloro-purins isN:C.O.Alk.

These new compounds, the dichloro-alkyloxypurins, may, as set forth inmy applications, Serial Nos. 668,644 and 668,647, filed concurrentlyherewith, be converted into hypoxanthin either directly by treating itwith a reducing agent or indirectly by firstdealkylizing and thensubmitting the resultant 6-oxy-2-S-dichloropurin to reduction. Thelatter method is not herein claimed, since it is covered in my aforesaidapplication, Serial No. 668,647. The former method is, however,specifically claimed herein; but the two methods are generically coveredin said application, Serial No. 668,644. As set forth in saidapplication, Serial No. 668,644, the new compounds,oxy-alkyl-dichloropurins, may by intermediate conversion into6-oXy-2-8-dichloropurin, followed by alkylization and final reduction,be converted into methylized hypo- Xanthins, such as1-7-dimethyl-hypoxanthin, (1-7-din1ethyl-6-oxypurin.)

I will now give in detail the direct method of preparing the hypoxauthinand, for the purpose of a fuller disclosure of the utility of the newcompound, the indirect method of arriving at the same compound.

Preparation of H'ypoxanthrn (a) Preparation of hypoccanthin from 245MH-chloro-6-eflt00cypu-rin.-One part of the finely powdereddichloro-ethoxypurin is added to ten parts hydrogen-iodid or hydriodicacid of the specific gravity 1.96, and after about onehalf part ofphosphonium-iodid or yellow phosphorous have been added the whole isfirst shaken for about an hour at ordinary temperature and then heatedon the waterbath until an almost colorless solution is formed. Oncooling the hydro-iodate of hypoxanthin is thrown out in the form ofbeautiful crystals. The entirequantity of this product is obtained byevaporating the hydrogen-iodid. The reaction takes place ac cording tothe equation:

After forming a concentrated aqueous solution of the hydro-iodate thehypoxanthin may be obtained therefrom by neutralizing with ammonia. Theproduct thus obtained is purilied by recrystallizin g from hot water,animal charcoal being added. The artificial compound thus preparedunites all the properties of natural hypoxanthin or (i-oxy-purin.

(1)) Preparation of hypoxantht'n front 2-8- cl ichloro-fi-oxy-pnrin.Ifin place of the ethoxy-dichloropurin we employ the simpleoxydichloropurin prod not, the 2-8-dichloro-6-oxypurin in the processunder (a), all other conditions remaining the same, the saidoxydichloropurin will lose its two chlorine atomsthat is to say,hypoxanthin or 6-oxypurin will again result.

. Preparation of 6-0wy-2-8-cZichZ0r0pm'in..- The2-8-dichloro-G-ethoxy-purin may be converted into the compound6-oxy-2-8-dichloropurin employed in process (19) by amineral acid,preferably a haloid acid. I find the following to be the best manner tocarry out this process: I mix powdered 2-8-dichloro-6-ethoxypurin withfive times its weight of fuming hydrochloric acid and heat the mixtureon the water-bath. Solution rapidly takes place,and thedifficultly-soluble 6oXy-2-8-dichloropurin is soon thrown out in theform of coarse crystals. The conversion will be completed in about ahalf-hour, after which the whole is diluted with about ten parts ofWater and allowed to cool, after which the mother-liquor is separatedfrom the crystals by filtration.

For the purpose of complete'purification the new bodyis converted intothe potassiumsalt, which ,is completely decolorized by recrystallization from hot water, to which some animal charcoal is added.The oxydichloropurin when recovered from the potassium salt formsbeautiful colorless acicular crystals having the formula C N I-I Ol O orHN-CO \Vhen heated to over 350, it decomposes and turns brown. tdissolves With'considerable difficulty even in hot water. It is moresoluble in hot alcohol. Its aqueous solution has an acid reaction anddecomposes carbonates. Its barium-salt crystallizes from a hot solutionof the same in excess of baryta water in fine needles, usuallyaggregated into fasces or bunches. Upon adding nitrate of silver to anammoniacal solution of the purin it forms a colorless amorphousprecipitate.

What I claim, and desire to secure by Lettcrs Patent of the UnitedStates, is-

1. As a step in the art of preparing oxy-purins and their derivatives,the process which consists in treating tri-chloropurin with an alkalinereagent, substantially as described.

2. As a step in the art of preparing oXy-purins and their derivatives,the process which consists in combining trichloropurin with an alcoholicsolution 'of alkali, cooling the mixture and adding water and thensupersaturating with acid.

3. As a step in the art of preparing oxy-purims and their derivatives,the process which consists in dissolving trichloropurin in ethylalcohol,cooling the mixture and adding a sodium solution and cooling, allowingthe mixture to stand at room temperature, then adding water and finallysupersaturating with an acid, all in the proportions substantially asset forth.

4:. As a step in the art of preparing oxy-purims and their derivatives,the process which consists in dissolving trichloropurin in ethylalcohol,cooling the mixture and addinga sodium solution and cooling, allowingthe mixture to stand at room temperature, then adding water and finallysupersaturating with acetic acid, all in the proportions substantiallyas set forth.

5. As a step in the art of preparing oxy-purims and their derivatives,the process which consists in dissolving trichloropurin in ethylalcohol,cooling the mixture and addingas odium solution and cooling, allowingthe mixture to stand at room temperature, then adding Water and finallysupersaturating with acetic acid and then evaporating the alcohol andrecrystallizing from hotalcohol.

-6. As a new chemical compound, 2-8-dichloro-o-alkyl-oxy-purin havingthe formula above indicated and which is soluble in alcohol and benzene,which softens at about 100, centigrade, and melts with decomposition ata high temperature.

7. As a new chemical compound, 2-S-dichloro-6-ethoxy-purin, having theformula above given, which is soluble in hot alcohol and benzene, butsoluble with difficulty in hot water, and which begins to soften atabout 190,centigrade,and melts with decomposition at about 200,centigrade.

8. The process of preparing hypoxanthins which consists in acting upon a2-8-dichloro- 6-alkyl-oxypurin with a reducing agent.

9. The process of preparing hypoxanthins which consists in treating2-S-dichloro-6-ethoxypurin with a reducing agent.

10. The process which consists in adding hydrogen-iodid andphosphonium-iodid to 2- 8-dichlOro-(S-ethoxypurin and shaking themixture at ordinary temperature, then heating the same on thewater-bath, then cooling, and, finally evaporating the hydrogen-iodid,all substantially as set forth.

In testimony whereof I affix my signature in presence of two witnesses.

EMIL FISCHER. Witnesses:

CHAS. H. DAY, HENRY HASPER.

